Histone hypoacetylation is associated with dopaminergic neurodegeneration in Parkinson's disease (PD), because of an imbalance in the activities of the enzymes responsible for histone ...(de)acetylation. Correction of this imbalance, with histone deacetylase (HDAC) inhibiting agents, could be neuroprotective. We therefore hypothesize that nicotinamide, being a selective inhibitor of HDAC class III as well as having modulatory effects on mitochondrial energy metabolism, would be neuroprotective in the lactacystin rat model of PD, which recapitulates the formation of neurotoxic accumulation of altered proteins within the substantia nigra to cause progressive dopaminergic cell death. Rats received nicotinamide for 28 days, starting 7 days after unilateral injection of the irreversible proteasome inhibitor, lactacystin, into the substantia nigra. Longitudinal motor behavioural testing and structural magnetic resonance imaging were used to track changes in this model of PD, and assessment of nigrostriatal integrity, histone acetylation and brain gene expression changes post‐mortem used to quantify nicotinamide‐induced neuroprotection. Counterintuitively, nicotinamide dose‐dependently exacerbated neurodegeneration of dopaminergic neurons, behavioural deficits and structural brain changes in the lactacystin‐lesioned rat. Nicotinamide treatment induced histone hyperacetylation and over‐expression of numerous neurotrophic and anti‐apoptotic factors in the brain, yet failed to result in neuroprotection, rather exacerbated dopaminergic pathology. These findings highlight the importance of inhibitor specificity within HDAC isoforms for therapeutic efficacy in PD, demonstrating the contrasting effects of HDAC class III inhibition upon cell survival in this animal model of the disease.
Open science badges
This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
Histone hypoacetylation, via misbalance of the activities of the enzymes responsible for histone acetylation (histone deacetylases (HDACs) and histone transferases (HATs)) is thought to contribute towards dopaminergic neurodegeneration in Parkinson's. Correction of this misbalance, with HDAC inhibitors (HDACIs) has been previously shown to be neuroprotective in animal models of the disorder. We tested the neuroprotective potential of the HDAC class III inhibitor, nicotinamide, in a rat model of Parkinson's. Rather than neuroprotection, we observed exacerbated neurodegeneration upon nicotinamide treatment, associated with over‐expression of numerous neurotrophic factors. These findings highlight the importance of HDACI isoform specificity for therapeutic efficacy in Parkinson's.
Open Science: This manuscript was awarded with the Open Materials Badge.
For more information see: https://cos.io/our-services/open-science-badges/
Polypharmacy is common in patients with nonalcoholic fatty liver disease (NAFLD) and previous reports suggest that NAFLD is associated with altered drug disposition. This study aims to determine if ...patients with NAFLD are at risk for altered drug response by characterizing changes in hepatic mRNA expression of genes mediating drug disposition (pharmacogenes) across the histological NAFLD severity spectrum. We utilize RNA-seq for 93 liver biopsies with histologically staged NAFLD Activity Score (NAS), fibrosis stage, and steatohepatitis (NASH). We identify 37 significant pharmacogene-NAFLD severity associations including CYP2C19 downregulation. We chose to validate CYP2C19 due to its actionability in drug prescribing. Meta-analysis of 16 independent studies demonstrate that CYP2C19 is significantly downregulated to 46% in NASH, to 58% in high NAS, and to 43% in severe fibrosis. Our data demonstrate the downregulation of CYP2C19 in NAFLD which supports developing personalized medicine approaches for drugs sensitive to metabolism by the CYP2C19 enzyme.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects over 500 million individuals who can experience anemia in response to oxidative stressors such as certain foods and drugs. Recently, the ...World Health Organization (WHO) called for revisiting G6PD variant classification as a priority to implement genetic medicine in low- and middle-income countries. Toward this goal, we sought to collect reports of G6PD variants and provide interpretations. We identified 1,341 G6PD variants in population and clinical databases. Using the ACMG standards and guidelines for the interpretation of sequence variants, we provided interpretations for 268 variants, including 186 variants that were not reported or of uncertain significance in ClinVar, bringing the total number of variants with non-conflicting interpretations to 400. For 414 variants with functional or clinical data, we analyzed associations between activity, stability, and current classification systems, including the new 2022 WHO classification. We corroborated known challenges with classification systems, including phenotypic variation, emphasizing the importance of comparing variant effects across individuals and studies. Biobank data made available by All of Us illustrate the benefit of large-scale sequencing and phenotyping by adding additional support connecting variants to G6PD-deficient anemia. By leveraging available data and interpretation guidelines, we created a repository for information on G6PD variants and nearly doubled the number of variants with clinical interpretations. These tools enable better interpretation of G6PD variants for the implementation of genetic medicine.
Display omitted
Interpreting the effect of sequence variation in G6PD can be used to predict which individuals are at risk for adverse drug reactions. By analyzing data from publications and databases, we provided interpretations for 186 G6PD variants of uncertain significance, bringing the total number of interpreted variants to 400.
Although many studies have investigated the disproportionate representation and negative experiences of justice-involved persons with mental illness (MI), we know less about probation/parole ...revocations among this population. Using statewide data and propensity score matching, we compare rates of rearrests and revocations between individuals with and without MI and assess the effectiveness of Specialized Mental Health Supervision (SMHS) in reducing the likelihood of revocation. In addition, we examine whether the risk score composition differs among participants of the SMHS program from clients with MI not placed on SMHS. Findings reveal that persons with MI are more likely to have a revocation, specifically for technical violations. In addition, SMHS does not significantly lower revocations after controlling for other caseload characteristics. Finally, those with higher risk scores were significantly less likely to be placed on SMHS caseloads. Considerations for SMHS implementation are discussed.
Response to Luzzatto et al Geck, Renee C; Powell, Nicholas R; Dunham, Maitreya J
American journal of human genetics,
11/2023, Letnik:
110, Številka:
11
Journal Article
MiRNAs regulate the expression of hepatic genes involved in pharmacokinetics and pharmacodynamics. Genetic variants affecting miRNA binding (mirSNPs) have been associated with altered drug response, ...but previously used methods to identify miRNA binding sites and functional mirSNPs in pharmacogenes are indirect and limited by low throughput. We utilized the high‐throughput chimeric‐eCLIP assay to directly map thousands of miRNA‐mRNA interactions and define the miRNA binding sites in primary hepatocytes. We then used the high‐throughput PASSPORT‐seq assay to functionally test 262 potential mirSNPs with coordinates overlapping the identified miRNA binding sites. Using chimeric‐eCLIP, we identified a network of 448 miRNAs that collectively target 11,263 unique genes in primary hepatocytes pooled from 100 donors. Our data provide an extensive map of miRNA binding of each gene, including pharmacogenes, expressed in primary hepatocytes. For example, we identified the hsa‐mir‐27b‐DPYD interaction at a previously validated binding site. A second example is our identification of 19 unique miRNAs that bind to CYP2B6 across 20 putative binding sites on the transcript. Using PASSPORT‐seq, we then identified 24 mirSNPs that functionally impacted reporter mRNA levels. To our knowledge, this is the most comprehensive identification of miRNA binding sites in pharmacogenes. Combining chimeric‐eCLIP with PASSPORT‐seq successfully identified functional mirSNPs in pharmacogenes that may affect transcript levels through altered miRNA binding. These results provide additional insights into potential mechanisms contributing to interindividual variability in drug response.
Background and Aim
Functional dyspepsia (FD), defined by unexplained pain or discomfort centered in the upper abdomen, is common. Diagnosis and treatment of FD based on the symptom‐based Rome ...criteria remains challenging. Recently, eosinophilia in the duodenum has been implicated in the pathophysiology of FD in adults, specifically increased eosinophils in early satiety and postprandial distress, but the association remains controversial. The aim of this study was to characterize upper gastrointestinal (GI) tract pathology, specifically duodenal eosinophilia, in an Australian cohort of patients with FD.
Methods
Patients prospectively referred for an upper GI endoscopy (n = 55; mean age, 49.6 years; 61.8% female) were stratified to FD cases (n = 33) and controls (n = 22) using Rome II criteria. All subjects completed a validated bowel symptom questionnaire. The eosinophil count per square millimeter in the duodenal bulb (D1) and second part (D2) was assessed and Helicobacter pylori status determined by gastric histology. Associations with clinical symptoms were assessed.
Results
Cases and controls were demographically similar. Duodenal eosinophilia was significantly increased in subjects experiencing early satiety (P = 0.01) and postprandial fullness (P = 0.001). This association was seen in D2 but not D1. Abdominal pain was associated with eosinophilia in both D1 (P = 0.02) and D2 (P = 0.005). Smoking was also associated with higher eosinophil counts in D2 (P = 0.007) and symptoms of early satiety (P = 0.02).
Conclusions
Duodenal eosinophilia occurs in a subset of FD. The potential role of duodenal eosinophils in FD has implications for diagnosis and therapeutic trials.
Coadministration with acid‐reducing agents (ARAs), including proton pump inhibitors (PPIs), histamine H2‐receptor antagonists (H2 blockers), and antacids has been demonstrated to reduce antiviral ...exposure and efficacy. Therefore, it is essential that US Food and Drug Administration (FDA) drug labels include recommendations to manage these drug–drug interactions (DDIs). This investigation analyzed information in FDA drug labels to manage DDIs between ARAs and antivirals approved from 1998 to 2019. To ascertain clinical adoption, we assessed whether FDA label recommendations were incorporated into current antiviral clinical practice guidelines. We identified 82 label recommendations for 43 antiviral approvals. Overall, 56.1% of recommendations were deemed clinically actionable, with the most common actionable management strategies being dose adjustment during coadministration (40.2%) and coadministration not recommended (9.8%). The sources informing DDI recommendations were clinical DDI studies (59.8%) and predictions of altered exposure (40.2%). Antivirals with low aqueous solubility were more likely to have label recommendations and were more commonly investigated using clinical DDI studies (P < 0.01). For recommendations informed by clinical DDI studies, changes in drug exposure were associated with actionable label recommendations (P < 0.01). The frequency of exposure changes in clinical DDI studies was similar across antiviral indications, but exposure changes were numerically higher for antacids (71.4%) relative to PPIs (42.9%) and H2 blockers (28.6%). Of DDI pairs identified within drug labels, 76.8% were included in guidelines, and recommended management strategies were concordant in 90.5% of cases. Our findings demonstrate that current regulatory oversight mostly (but not completely) results in actionable label recommendations to manage DDIs for high‐risk antivirals.
Context: The Rural Adversity Mental Health Program (RAMHP) connects people who need mental health assistance in rural and remote New South Wales (NSW), Australia with appropriate services and ...resources. In 2016, RAMHP underwent a comprehensive reorientation to meet new state and federal priorities. A full assessment of program data collection methods for management, monitoring and evaluation was undertaken. Reliable data were needed to ensure program fidelity and to assess program performance.
Issues: The review indicated that existing data collection methods provided limited and unreliable information, were inconvenient for RAMHP coordinators to use and unsuited to their itinerant role. A mobile collection tool (app) was developed to address RAMHP activity data needs. A design and implementation process was followed to optimise data collection and to ensure the successful use of the app by coordinators.
Lessons learned: The early planning investment was worthwhile, the app was successfully adopted by the coordinators and a much improved data collection capability was achieved. Moreover, data capture increased, while errors decreased. Data are more reliable, specific, timely and informative and are used for strategic and operational planning and to demonstrate program performance.
The reader will come to appreciate that:•Race-based disparities in pulse oximetry have been reported in large retrospective database studies involving adults and recently in pediatric ...populations.•Pulse oximeters overestimate oxygen saturation in Black compared to other races, particularly in hypoxic states.•Role of skin pigmentation and other dermatological factors that may vary between racial groups has not been evaluated.•Defining mechanisms of this inaccuracy is critical to addressing this disparity in pulse oximeter performance.
Race-based and skin pigmentation-related inaccuracies in pulse oximetry have recently been highlighted in several large electronic health record-based retrospective cohort studies across diverse patient populations and healthcare settings. Overestimation of oxygen saturation by pulse oximeters, particularly in hypoxic states, is disparately higher in Black compared to other racial groups. Compared to adult literature, pediatric studies are relatively few and mostly reliant on birth certificates or maternal race-based classification of comparison groups. Neonates, infants, and young children are particularly susceptible to the adverse life-long consequences of hypoxia and hyperoxia. Successful neonatal resuscitation, precise monitoring of preterm and term neonates with predominantly lung pathology, screening for congenital heart defects, and critical decisions on home oxygen, ventilator support and medication therapies, are only a few examples of situations that are highly reliant on the accuracy of pulse oximetry. Undetected hypoxia, especially if systematically different in certain racial groups may delay appropriate therapies and may further perpetuate health care disparities. The role of biological factors that may differ between racial groups, particularly skin pigmentation that may contribute to biased pulse oximeter readings needs further evaluation. Developmental and maturational changes in skin physiology and pigmentation, and its interaction with the operating principles of pulse oximetry need further study. Importantly, clinicians should recognize the limitations of pulse oximetry and use additional objective measures of oxygenation (like co-oximetry measured arterial oxygen saturation) where hypoxia is a concern.
PDF
